The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

Robert Carreras-Torres, Mattias Johansson, Valérie Gaborieau, Philip Haycock, Kaitlin Wade, Caroline Relton, Richard Martin, George Davey Smith, Paul Brennan

Research output: Contribution to journalArticle (Academic Journal)peer-review

182 Citations (Scopus)
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Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.

Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance and type 2 diabetes, in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk within a series of 7,110 pancreatic cancer cases and 7,264 controls using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4).

Results: A likelihood-based MR approach indicated a robust causal association of increasing body-mass index (BMI) with pancreatic cancer risk (OR [95%CI]= 1.34 [1.09-1.65]; for each standard deviation (SD) increase in BMI (4.6 Kg/m2
)). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR [95%CI]= 1.66 [1.05-2.63]; per SD (44.4 pmol/l)). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Assessment of potential unknown pleiotropic effects using a weighted-median approach and MR-Egger sensitivity analyses did not indicate that pleiotropy was an important source of bias.

Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.
Original languageEnglish
Article numberdjx012
Number of pages9
JournalJournal of the National Cancer Institute
Issue number9
Early online date28 Apr 2017
Publication statusPublished - 1 Sept 2017

Structured keywords

  • ICEP


  • Obesity
  • metabolic factors
  • pancreatic cancer
  • two-sample Mendelian randomization


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